Rectal adenocarcinomas are among the most frequent malignant tumors in the Western World. Surgery, including total mesorectal resection, is the primary treatment for rectal carcinomas. In locally advanced stages of this disease, radiation or combined radiochemotherapy is mandatory. Whether radiochemotherapy should be administered prior to surgery (neoadjuvant) or after resection of the primary tumor (adjuvant), however, is still a matter of controversy (Sauer R. (2002) Pathol Oncol Res 8, 7-17; Pahlman et al. (1998) Eur J Cancer 34, 438-48; Nelson et al. (2001) N Engl J Med 345, 690-2). The decision to administer neoadjuvant radiochemotherapy relies primarily on the depth of tumor infiltration, which, in specialized centers is determined pre-therapeutically by rectal ultrasound (Liersch et al. (2003) Chirurg 74, 224-34; Hunerbein et al. Ann Surg (1997) 225, 432-8; Adams et al. (1999) Dis Colon Rectum 42, 159-66; Glaser et al. (1990) Br J Surg 77, 883-7). Neoadjuvant regimens might be particularly attractive (i) because a priori not curatively resectable tumors can be down-sized to achieve the undisputed benefit of tumor cell free surgical margins (R0-resection), (ii) because preoperative treatment reduces tumor burden and, therefore, might increase the possibility for sphincter preservation, and (iii) because radiochemotherapy cannot be applied when postoperative clinical complications occur.
However, the response of individual tumors to radiochemotherapy is not uniform. This poses a considerable clinical dilemma because patients with a priori resistant tumors could be spared exposure to radiation and DNA-damaging drugs, treatments that are associated with substantial side effects. In such cases surgery could be scheduled without delay. Alternatively, different neoadjuvant treatment modalities including additional chemotherapeutics could be pursued. It would therefore be of significant clinical relevance to identify predictive markers of cancer response to neoadjuvant radiochemotherapy.
Accordingly, numerous groups have employed targeted approaches to correlate expression levels of candidate genes in response to radiation, different chemotherapeutic drugs, and combinations of radiation and chemotherapy (for review see Pasche et al. (2002) Best Pract Res Clin Gastroenterol 16, 331-45; Adlard et al. (2002) Lancet Oncol 3, 75-82). The selections of candidate genes primarily included genes required for drug metabolism, drug activation, drug resistance, and DNA damage repair, and oncogenes and tumor suppressor genes involved in cell cycle control. Unfortunately, these candidate gene approaches have not materialized into sound pre-therapeutic predictors of response to radiochemotherapy. See, e.g., Okonkwo et al. (2001) Oncol Rep 8, 497-500; Saw et al (2003) Dis Colon Rectum 46, 192-202; Spitz et al. (1997) Clin Cancer Res 3, 1685-90; Luna-Perez et al. (1998) Ann Surg Oncol 5, 203-8; Elsaleh et al. (2000) Radiother Oncol 56, 239-44; Diez et al (2003) Oncology 64, 213-9; Scott et al. (1998) Eur J Surg Oncol 24, 169-73. There remains a need to establish reliable, clinically useful, predictors of radiochemosensitivity of rectal adenocarcinomas.
Parallel profiling of global gene expression levels based on microarray technologies has emerged as a powerful tool to monitor the transcriptome of cancer cells for tumor classification and prognosis (Rosenwald et al. (2002) N Engl J Med 346, 1937-47; van't Veer et al. (2002) Nature 415, 530-6; Iizuka et al. (2003) Lancet 361, 923-9; Bertucci et al. (2001) Lancet Oncol 2, 674-82; Yeoh et al. (2002) Cancer Cell 1, 133-43). In addition, the power of gene expression profiling as a predictor of drug response has been explored in several model systems, including the NCI-60 cancer cell line panel (Staunton et al. (2001) Proc Natl Acad Sci USA 98, 10787-92; Scherf et al. (2000) Nat Genet 24, 236-44) and tumor xenografts (Zembutsu et al. (2002) Cancer Res 62, 518-27). The results of these studies provide evidence that at least for some tumors and a subset of drugs, pre-therapeutic gene expression profiles might predict treatment response.
The present inventors have analyzed gene expression profiles of rectal adenocarcinomas, and have identified genes whose expression is correlated with responsiveness of the tumors to radiochemotherapy (e.g., neoadjuvant radiochemotherapy). Combinations comprising probes specific for these genes can be used in, e.g., diagnostic and experimental methods.